Journal
JOURNAL OF INTERNAL MEDICINE
Volume 281, Issue 4, Pages 383-397Publisher
WILEY
DOI: 10.1111/joim.12589
Keywords
apolipoprotein B-100; atherosclerosis; epitopes; T-cell; vaccination
Categories
Funding
- Swedish Heart-Lung Foundation
- Karolinska Institute Cardiovascular Program Career Development Grant
- CERIC Linnaeus Program [349-2007-8703]
- Swedish Research Council-Medicine [521-2012-2440, K2013-65X-06816]
- Stockholm County Council (ALF)
- European Union [603131]
- Molstroke and AtheroRemo
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Background and ObjectivesThe T-cell response to low-density lipoprotein (LDL) in the vessel wall plays a critical role in atherosclerotic plaque formation and stability. In this study, we used a new translational approach to investigate epitopes from human apolipoprotein B100 (ApoB100), the protein component of LDL, which triggers T-cell activation. We also evaluated the potential of two selected native ApoB100 epitopes to modulate atherosclerosis in human ApoB100-transgenic Ldlr(-/-) (HuBL) mice. Methods and ResultsHuBL mice were immunized with human atherosclerotic plaque homogenate to boost cellular autoimmune response to tissue-derived ApoB100 epitopes. In vitro challenge of splenocytes from immunized mice with a library of overlapping native peptides covering human ApoB100 revealed several sequences eliciting T-cell proliferation. Of these sequences, peptide (P) 265 and P295 were predicted to bind several human leucocyte antigen (HLA) haplotypes and induced high levels of interferon (IFN)-. Vaccination of HuBL mice with these peptides mounted a strong adaptive immune response to native ApoB100, including high levels of epitope-specific plasma IgGs. Interestingly, P265 and P295 vaccines significantly decreased plaque size, reduced macrophage infiltration and increased IgG1 deposition in the plaques. Purified IgGs from vaccinated mice displayed anti-inflammatory properties against macrophages invitro, reducing their response to LPS in a dose-dependent manner. ConclusionWe identified two specific epitopes from human native ApoB100 that trigger T-cell activation and protect HuBL mice against atherosclerosis when used in a vaccine. Our data suggest that vaccination-induced protective mechanisms may be mediated at least in part through specific antibody responses to LDL that inhibit macrophage activation.
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